Tens of thousands of people may have been seriously harmed by the painkiller Vioxx, and many more may be at risk from taking other popular drugs of the same class, known as COX-2 inhibitors, two experts wrote in papers released yesterday by the New England Journal of Medicine.
Cleveland Clinic researcher Eric J. Topol wrote that the recently terminated study that led to the recall of Vioxx last week indicates that "it is possible that there are tens of thousands of patients who have had major adverse events attributable to" the drug. In an interview, he estimated the number of people who have had heart problems and strokes as a result of taking Vioxx to be 30,000 to 100,000.
Another study of possible heart problems and strokes stemming from the drug projected that it has caused more than 27,000 serious adverse reactions. That estimate was made recently by a Food and Drug Administration safety official based on a study of about 1.4 million patients at Kaiser Permanente health care facilities.
Merck & Co. President Raymond V. Gilmartin declined to comment on the estimates. A company spokesperson said Topol's estimate "goes beyond the data" and inaccurately extrapolates results from one study to the entire universe of Vioxx users.
Merck withdrew the drug from the market last week after a large, placebo-controlled study found a significantly increased risk of cardiovascular disease and strokes in patients given Vioxx as part of a study to see whether it would prevent colon polyps.
The voluntary recall has led to intense focus on the other COX-2 inhibitors, including the painkiller Celebrex, made by Pfizer Inc. The European Medicines Agency in London said yesterday that it would review safety data on all drugs of the class; the FDA has indicated previously it will be doing the same. Celebrex and Vioxx have been among the most widely prescribed medications in the United States in recent years.
In the second New England Journal of Medicine article, Garret A. FitzGerald of the University of Pennsylvania wrote that his research into the way COX-2 inhibitors work leads him to believe Celebrex and several others could have negative cardiovascular effects similar to those linked to Vioxx. In addition, FitzGerald wrote that clinical trials of all the COX-2 inhibitors showed signs of some increased cardiovascular risk.
With the new results from the Merck polyp study, FitzGerald wrote, the "burden of proof" has shifted and all the COX-2 inhibitors should be viewed as risky.
"It seems to be time for the FDA urgently to adjust its guidance to patients and doctors to reflect this new reality," he wrote.
Pfizer Vice President Mitch Gandelman said yesterday that clinical trials have shown that Celebrex does not pose the same cardiovascular risks as Vioxx, and that patients have no reason to be concerned.
"It's hard to comprehend how two drugs in the same class could be so different," Gandelman said. "But they are each in a subclass of their own, and those different chemical structures translate into a different safety profile."
Gandelman said Celebrex is being studied in three long-term clinical trials in which patients have taken the drug for as many as three years. He said the increased risk of heart attacks and strokes found in the Vioxx polyp study at 18 months have not been found with Celebrex.
Both commentaries in the journal took the FDA to task for not being sufficiently aggressive in making sure that Vioxx and other COX-2 inhibitors are safe. Topol, in particular, was highly critical of the agency for allowing Merck to aggressively advertise Vioxx despite concerns going back to 2000 about the increased risk of cardiovascular disease. The papers had been scheduled for publication on Oct. 21 but were released early by the journal yesterday.
"The senior executives at Merck and the leadership at the FDA share responsibility for not having taken appropriate action and not recognizing that they are accountable for the public health," Topol wrote.
FitzGerald wrote: "Only the FDA can provide unbiased and informed guidance; it has a role to play beyond watchful waiting. In the absence of such guidance, what should physicians and patients do?"
In a statement yesterday, Merck called Topol's commentary "flawed in many important aspects." In particular, the company said Topol had misrepresented Merck's efforts to get firm information about heart and stroke risks linked to Vioxx.
The statement said that beginning in 2000, the company undertook three randomized clinical trials to collectively assess that risk, and one of them was the colon polyp study that revealed the increased danger. After the independent safety experts monitoring the study recommended that it be terminated, Merck pulled Vioxx from the market.